Hypermethylation of the CTRP9 promoter region promotes Hcy induced VSMC lipid deposition and foam cell formation via negatively regulating ER stress

Hypermethylation of the CTRP9 promoter region promotes Hcy induced VSMC lipid deposition and foam cell formation via negatively regulating ER stress

Abstract To provide a theoretical basis for the prevention and treatment of atherosclerosis (As), the current study aimed to investigate the mechanism underlying the effect of homocysteine (Hcy) on inducing the lipid deposition and foam cell formation of the vascular smooth muscle cell (VSMC) via C1...

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Bibliographic Details
Published in:Scientific reports 2023-11, Vol.13 (1), p.19438-19438, Article 19438
Main Authors: Wang, Xiuyu, Ma, Xing, Zeng, Yue, Xu, Lingbo, Zhang, Minghao
Format: Article
Language:eng
Subjects:
Animal models
Aorta
Apolipoprotein E
Arteriosclerosis
Bisulfite
Cholesterol
CpG islands
Diet
DNA methylation
DNMT1 protein
Down-regulation
Endoplasmic reticulum
Gene expression
Homocysteine
Immunofluorescence
Inositol
Kinases
Lipids
Methionine
Molecular modelling
Oils & fats
Plasmids
Protein expression
Proteins
Regulatory sequences
Serum levels
Smooth muscle
Sterols
Therapeutic targets
Transfection
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Summary:Abstract To provide a theoretical basis for the prevention and treatment of atherosclerosis (As), the current study aimed to investigate the mechanism underlying the effect of homocysteine (Hcy) on inducing the lipid deposition and foam cell formation of the vascular smooth muscle cell (VSMC) via C1q/Tumor necrosis factor-related protein9 (CTRP9) promoter region Hypermethylation negative regulating endoplasmic reticulum stress (ERs). Therefore, apolipoprotein E deficient (ApoE −/− ) mice were randomly divided into the control [ApoE −/− + normal diet (NC)] and high methionine [ApoE −/− + (normal diet supplemented with 1.7% methionine (HMD)] groups (n = 6 mice/group). Following feeding for 15 weeks, the serum levels of Homocysteine (Hcy), total cholesterol (TC), and triglyceride (TG) were measured using an automatic biochemical analyzer. HE and oil red O staining were performed on the aorta roots to observe the pathological changes. Additionally, immunofluorescence staining was performed to detect the protein expression levels of CTRP9, glucose-regulated protein 78 kD (GRP78), phosphorylated protein kinase RNA-like ER kinase (p-PERK), activating transcription factor 6a (ATF6a), phosphorylated inositol-requiring enzyme-1α (p-IRE1α), sterol regulatory element binding proteins-1c (SREBP1c) and sterol regulatory element binding proteins-2 (SREBP2) in VSMC derived from murine aortic roots. In vitro, VSMC was stimulated with 100 μmol/l Hcy. After transfection of plasmids with overexpression and interference of CTRP9, ERs agonist (TM) and inhibitor (4-PBA) were given to stimulate VSMC cells. HE staining and oil red O staining were used to observe the effect of Hcy stimulation on lipid deposition in VSMC. Additionally, The mRNA and protein expression levels of CTRP9, GRP78, PERK, ATF6a, IRE1α, SREBP1c, and SREBP2 in VSMC were detected by RT-qPCR and western blot analysis, respectively. Finally, The methylation modification of the CTRP9 promoter region has been studied. The NCBI database was used to search the promoter region of the CTRP9 gene, and CpG Island was used to predict the methylation site. After Hcy stimulation of VSMC, overexpression of DNMT1, and intervention with 5-Azc, assess the methylation level of the CTRP9 promoter through bisulfite sequencing PCR (BSP). The results showed that the serum levels of Hcy, TC, and TG in the ApoE −/− + HMD group were significantly increased compared with the ApoE −/− + NC group. In addition, HE staining and oil red O st
ISSN:2045-2322
2045-2322